This project is in response to a request from NIDA for studies on opioid agonists that are found in commonly abused prescription pain medications. Recent data suggest a substantial increase in abuse of prescription opioid analgesics that are used to treat several clinical concerns, most notably pain. The overall goal of this project is to examine the pharmacodynamics of these opioid agonists. To address this goal, the project has 2 Specific Aims. Specific Aim 1 is to examine the relative analgesic potency of and production of tolerance to opioid agonists commonly found in prescription pain medications. Specific Aim 2 is to determine the relative efficacy of these opioid agonists and evaluate the role of efficacy in the development of analgesic tolerance and the regulation of mu-opioid receptors. The opioids to be studied were chosen based on the most recent SAMHSA data in the DAWN survey and the National Survey on Drug Use. The project will test 3 hypotheses. Hypothesis 1 is that the efficacy of opioid agonists determines the development of tolerance. Specifically, high efficacy agonists will produce less tolerance than equi-effective doses of low efficacy agonists in the intact mouse. Hypothesis 2 is that the efficacy of opioid agonists determines the regulation of mu-opioid receptor density in spinal cord of the intact mouse. Specifically, high efficacy agonists will reduce mu-opioid receptor density in the mouse spinal cord, whereas low efficacy agonists will either not affect, or increase mu-opioid receptor density. Hypothesis 3 is that directly changing the efficacy of an opioid ligand will alter the magnitude of tolerance and regulation of mu-opioid receptor density in spinal cord of the intact mouse. It is anticipated that irreversible alkylation of mu-opioid receptors will reduce the efficacy of opioid agonists and will increase opioid tolerance at equi-effective doses and reduce regulation of mu- opioid receptor density. Overall, the results of this project will provide new and important information on the pharmacodynamics and mechanism of action of a group of opioid analgesics that are potential drugs of abuse. [unreadable] [unreadable] [unreadable]